Changes in the microcirculation at the superficial and deeper levels in lymphoedema: the effects and results of massage, compression, exercise and benzopyrones on these levels during treatment.

This review starts with a brief description of the pioneering work done by J.R. Casley-Smith when he looked at the pathophysiological changes that occur, and transport from the blood vessels, through the interstitium to the lymphatics and lymphatic uptake, with the electron microscope. Collaboration with, and further work by many colleagues producing a better understanding of lymphatic drainage, have led to this work being applied in the treatment of lymphoedema.

Benzo-pyrones in the treatment of lymphoedema.

Fifty clinical trials of 4 benzo-pyrones in the treatment of lymphoedema, by over 37 authors in 8 countries, are reviewed: 38 oral and 12 topical (11 and 6 of these, added to other therapies). Oral benzo-pyrones reduced oedema, symptoms (in almost all) and inflammation (SAI). These were significant and clinically important. There were no significant differences between arms and Grades 1 and 2 legs. Combining these 20 trials gave mean annual reductions of 55% of oedema (SE: 7.8%; 95% Confidence Interval: 40% to 71%) (p<0.001). Four trials of elephantitic legs gave 17% (4.8%; 7.6% to 27%), significantly less (p<0.01). Meta-analyses, tested by omitting non-double-blind or non-peer-reviewed trials, were robust. The greater the oedema, the greater the rate of reduction-lessening as time passed and the oedema reduced: annual reduction=37%x(79%) Period (p=0.01). Reductions varied with the molar dose (p=10(-8)): =0.10% (SE 0.013%) Dose (mg of coumarin or molar equivalent of other drugs). Topical coumarin also reduced oedema and symptoms. The results of some other therapies were improved by oral or topical benzo-pyrones 15% to 22% over a month and 0% to 78% over a year. These drugs are slow, but effective, cheap and convenient. Because of their slowness, compression garments are unnecessary. They were seldom used in trials. Side-effects are minimal. Only oral coumarin may cause idiosyncratic hepatitis (3 per 1,000). Topical coumarin does not, nor other benzo-pyrones.

Treatment for lymphedema of the arm--the Casley-Smith method: a noninvasive method produces continued reduction.

BACKGROUND: This paper gives an outline of the Casley-Smith method for the treatment of lymphedema of the arm. It includes a brief summary of the development of manual techniques and the terminology applied to them. METHODS: The four principles of this method are skin care, manual lymphatic drainage, compression in the form of bandaging and/or garments, and exercise. The massage techniques, especially where they differ from other schools, are described in some detail, as are the principles that apply in compression and maintenance of reduction in lymphedema. RESULTS: The results of this method have been analyzed both in Australia and in the United States and are discussed briefly. Mention is made of the benefits of the benzopyrones, which have been used for many years, when added to the above treatment. Both benzopyrones and exercise will produce a continued reduction after the treatment course. They are particularly useful in a less compliant patient. It is stressed that the effect of patient compliance, particularly after treatment, makes a great difference to the ongoing success of the regime. CONCLUSIONS: A comparison is drawn between the efficacy of various current treatments and their cost. This shows that this combined and conservative method of treatment should be considered before recourse to pumps or surgery. The latter seldom achieve the results of decongestive lymphatic drainage, and, in the long term, they are more expensive. Certain preventive measures may be indicated following, e.g., mastectomies. Prevention of the onset of lymphedema is of extreme importance. However, a return to as normal a lifestyle as possible by the patient is also essential. The earlier treatment begins after the onset of lymphedema, the better the prognosis for the patient. Lymphedema can and should be treated.

Treatment of lymphedema by complex physical therapy, with and without oral and topical benzopyrones: what should therapists and patients expect.

Using previously presented data, from an open multi-centered trial, the Medians and Third Quartiles were calculated for the overall edema reductions the "average" patient received from an "average" therapist using Complex Physical Therapy (CPT) on 628 lymphedematous limbs. These data provide therapists and patients a general guideline as to the minimal reductions which can be expected in three quarters of patients from average therapists, using CPT with or without the administration of benzo-pyrones. Benzo-pyrones were considered separately: oral (given for three months before and for 11 months after the course of CPT) and topical (during and after CPT). Depending on which measure of edema and its alterations were used, these reductions increased those from CPT alone from 130% to 200% and, after one year, between 150% to 300%. Whereas the effects of oral and topical benzo-pyrones were not statistically different, their combined usage was more effective than use of either alone.

Lymphedema initiated by aircraft flights.

INTRODUCTION: This study arose because a number of patients volunteered that flying had triggered, or worsened, their lymphedema. The nature of lymphedema is discussed, including the pre-lymphedematous latent-phase. In this phase the limb is clinically normal, but lymphostatic. There are many of the alterations found in clinical lymphedema involving blood vessels, tissues, lymphatics, and proteolytic cells. Since edema itself impairs many of the safety factors against edema (increased tissue hydrostatic pressure, dilution of proteins in tissue fluid, increased lymphatic transport, and increased proteolysis), any edema occurring in such a limb is likely to persist as chronic lymphedema. METHOD & RESULTS: Questionnaires were sent to 1,020 patients with lymphedema; 749 replied, with 531 answering a question about what triggered the condition. It was present from near birth in 41, but developed later in 490 (163 post-mastectomy lymphedemas, and 136 primary and 191 secondary leg lymphedemas). In 27 of the 490, it started during an aircraft flight (15 legs and 12 arms). In addition, flying caused existing lymphedema to permanently worsen in 23 arms and 44 legs in the 749 respondents. Some typical case histories are given. CONCLUSIONS: Because of its frequency in arms and legs, it is highly likely that this triggering, or worsening, of lymphedema is produced by lowered cabin pressure. Obstruction of veins and lymphatics, and reduced muscle pumping, may contribute to this in the legs. Using additional compression for existing lymphedema, or limbs at risk, would prevent this. If it occurs, it should be treated by additional compression, using inflated splints or pressure bandages.

Alterations of untreated lymphedema and it's grades over time.

Lymphedema is assumed to increase in amount and Grade with time. This work verifies that assumption, and may be helpful in persuading patients to undergo treatment and provides prognosis for likelihood of future disability. Before-treatment volumes of lymphedema/normal, Grades and durations' are compared in 231 postmastectomy arm, 74 primary leg, and 103 secondary leg lymphedemas. These were the first, consecutive, unilateral lymphedemas to receive treatment at 25 clinics whose therapists we had trained. Amounts of lymphedema increased with time, as did Grades. Arms increased more rapidly (p = 0.01) than secondary or primary legs, which did not differ from each other (linear regressions: 1.8 (0.34), 0.63 (0.20) and 0.68 (0.38) %/year, respectively). The Grades of primary lymphedemas increased more slowly than those of either secondary arms (p = 0.02) or secondary legs (p = 0.03), which did not differ from each other (regressions: 0.010 (0.0048), 0.038 (0.0063) and 0.032 (0.0048) Grades/year, respectively). Increase of lymphedema with Grade was less for secondary legs than for primary legs (p = 0.004) or arms (p = 0.009), which did not differ significantly (regressions: 9.9 (3.5), 35 (8.7) and 25 (3.4) %/Grade, respectively). Thus, arms increased more rapidly in size than primary or secondary legs; primary legs remained in each Grade longer--and got larger in them--than did secondary legs. This relative lack of fibrosis in primary lymphedema permitted greater amounts of edema and accorded well with histopathological studies. The increases described with duration were not caused simply by patient aging. Whereas both duration and the age at the onset of lymphedema were significant for the arms, only duration was significant for the legs. Even in the arms duration was much more important than age.

Measuring and representing peripheral oedema and its alterations.

Correlation was very good between 1,500 simultaneous measurements of peripheral lymphoedema (arms and legs) by water displacement and by calculating volumes from circumferences, but in the legs "circumferences" gave only half the absolute amount of oedema when compared with "water displacement." For 150 arms, however, each method provided almost identical values for oedema. Arms when oedematous are fairly uniformly swollen; legs, on the other hand, are typically more oedematous distally. Circumference measurements accordingly include portions of nearly normal (i.e., minimally or nonoedematous) leg; water displacement by contrast measures only the oedematous, distal region. When only the circumferences of the lower legs were taken into consideration, the amount of oedema as measured by water displacement were almost identical. Nonetheless, measuring the proximal, more normal, or nonoedematous regions of the leg is critical for assessing treatment by physical methods (e.g., complex physical therapy). The various equations representing oedema can be greatly affected by errors in the initial, final or normal measured volumes. Relative errors differ as these variables alter. Many of the equations are non-linear, i.e., small alterations in one variable may produce widely differing results depending on the other variables. Problems in the use of an abnormal contralateral or "normal" limb as a reference point are discussed. The best equation to use in bilateral oedema is "Difference in Volume/Initial Volume"; in unilateral oedema the best equation is "Difference in Oedema/Normal". "Change in Oedema" i.e., "Difference in Oedema/Initial Oedema" is best derived from the Means of other equations.

Treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone (coumarin).

OBJECTIVE: To study efficacy of treatment of filarial lymphoedema and elephantiasis with 5,6-benzo-alpha-pyrone. DESIGN: Randomised, double blind, placebo controlled study with matching for grade and duration of disease, age, and sex. Treatment was given for 367 days, and subjects were followed up for another year. SETTING: A town in Shandong Province, China. SUBJECTS: 104 men and women with chronic unilateral filarial lymphoedema or elephantiasis of the leg: 64 were randomised to benzopyrone and 40 to placebo. By the end of the study 19 patients had dropped out of the treatment group and two out of the placebo group. INTERVENTIONS: Two 200 mg tablets of 5,6-benzo-alpha-pyrone or two placebo tablets given daily. MAIN OUTCOME MEASURES: Volumes of the affected and normal legs estimated every three months, and daily listing of any side effects. RESULTS: Benzopyrone reduced oedema for all grades of lymphoedema during the year of treatment (pW0.001) and the follow up year (p = 0.026). During treatment the mean monthly reductions in leg volume were 0.62% (95% confidence intervals 0.4% to 0.85%), 1.1% (0.71% to 1.6%), and 1.6% (0.89% to 2.3%) of the volume of the normal leg for grades 1, 2, and 3-5 (elephantiasis) of lymphoedema respectively. During follow up the mean monthly reductions were 0.18% (0.01% to 0.35%), 0.54% (0.27% to 0.82%), and 0.87% (0.51% to 1.2%). At the end of the trial the total reduction in oedema was 100%, 95%, and 45% for grades 1, 2, and 3-5. Symptoms and complications were considerably reduced, including attacks of secondary acute inflammation, while side effects were minor and disappeared after one month. In the placebo group there were no changes in the severity of lymphoedema. CONCLUSIONS: 5,6-benzo-alpha-pyrone reduces the oedema and many symptoms of filarial lymphoedema and elephantiasis. It has few side effects, and its relatively slow action makes it ideal for use without compression garments.

Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone.

BACKGROUND: Benzopyrones can reduce the volume of high-protein edema fluid by stimulating proteolysis. These compounds provide a method for removing excess protein and its consequent edema and reduce its clinical sequelae, such as chronic inflammation and secondary infections. METHODS: We conducted a randomized, double-blind, placebo-controlled, crossover trial of 5,6-benzo-[alpha]-pyrone in 31 patients with postmastectomy lymphedema of the arm and 21 patients with lymphedema of the leg of various causes (this agent, also known as 56 BaP, 1,2-benzopyrone, or coumarin, is not an anticoagulant). The patients received 400 mg of the active drug or placebo, each for six months. RESULTS: During the placebo period, lymphedema often worsened, especially in the arms. Measurements of limb volume showed that the active drug reduced the mean amount of edema fluid in the arms from 46 percent above normal to 26 percent above normal (P < 0.001) and the amount in the legs from 25 percent to 17 percent above normal (P < 0.001). The circumference of the arms was reduced from 17 percent to 13 percent above normal, and the circumference of the legs from 11 percent to 7 percent above normal (P < 0.001). The softness of the limb tissue was increased (P < 0.001), and elevated skin temperatures were reduced (P < 0.001). There were fewer attacks of secondary acute inflammation (P = 0.01). Bursting pains and feelings of hardness were decreased, as were feelings of tightness, tension, swelling, and heaviness; limb mobility also improved. The active drug was preferred to the placebo by 93 percent of the patients (P < 0.001). Side effects--mild nausea or diarrhea--occurred in seven patients taking the active drug. None withdrew from the trial, and the side effects disappeared after the first month of therapy. CONCLUSIONS: 5,6-Benzo-[alpha]-pyrone results in slow but safe reduction of lymphedema of the extremities.

Reduction of filaritic lymphoedema and elephantiasis by 5,6 benzo-alpha-pyrone (coumarin), and the effects of diethylcarbamazine (DEC).

Chronic filaritic lymphoedema and elephantiasis, in India, were treated orally with 5,6 benzo-alpha-pyrone (56 BaP; 1,2 benzo-alpha-pyrone; coumarin) in a double-blind, randomized, matched-group trial. Each group finally contained 40-55 patients. Patients were observed for about 2 years (ranging from 6 to 45 months, with 75% completing the 2 years). The 56 BaP slowly, but very significantly (P < 0.0001), reduced all grades of lymphoedema and elephantiasis. Two thirds of the oedema was lost by grade 2 over 2 years. Grades 3 to 5 were reduced by a fifty over that time. The greater the initial oedema, the greater was its rate of resolution. A slowly worsening condition thus became a slowly improving one. Slowness has its advantages: compression stockings, that are impractical in hot, wet or dirty conditions, are not necessary. The slowly remodelling fibrous tissue, while lessening in amount, is still able to hold the tissues together. The 56 BaP considerably improved many symptoms and complications, particularly bursting-pains, inflammation and ulcers. It is cheap and of very low toxicity. Diethylcarbamazine (DEC) was studied with and without 56 BaP. DEC alone gave some reduction of the oedema, but this was much smaller than that with 56 BaP. It considerably worsened the reductions by 56 BaP, while 56 Bap slightly improved those by DEC and reduced the fever caused by DEC. Together, they reduced feelings of swelling and bursting-pain, fungal infections, lymphangitis and lymphadenitis more than when used alone.

Topical treatment of acute hindlimb lymphedema of the rat using a troxerutin-phosphatidylcholine complex in liposomal-like microdispersion.

A new reversible complex between troxerutin and phosphatidylcholine (85-90mg/kg per day), in the form of a liposome-like water microdispersion, was topically applied to the rat thigh in an experimental counterpart of acute lymphedema. After four days there was 75% less hindlimb edema (mean decrease 40% of normal compared to control 10% of normal) in the treated compared with the untreated rats. These findings suggest that this drug preparation may be useful to minimize acute peripheral lymphedema in patients.

A model of the factors affecting interstitial volume in oedema. Part III: Partial derivatives and integrals at various volumes.

The effects of the individual Factors controlling interstitial volume vary between the different steady-states. Partial derivatives of volume with respect to each Factor show only the effects near the steady-state. In passing from one steady-state to another, these partial derivatives vary greatly. The total effects of a Factor are those of the integral of the partial derivative from the initial steady-state to the final one. The simplest way to measure a Factor's total effect is by setting it to zero and observing the difference in tissue volume when the model is perturbed. Thus, to find the effect of proteolysis in lymphoedema, for example, let proteolysis = 0 and compare the final volume in lymphoedema with that when proteolysis is allowed to occur. While the effect of proteolysis is important in lymphoedema, it is of minimal importance in trauma or normal condition. It is again important if proteolysis is increased by benzo-pyrones. There is little correlation between a partial derivative at a steady-state and the integral of this from normal to the state. In low-to-moderate oedemas, many Factors influence the fluid volume. When this volume becomes very large, all Factors except tissue hydrostatic pressure decrease in importance. Tissue hydrostatic pressure can increase indefinitely and is the ultimate reason that oedemas do not increase without limit.

A model of the factors affecting interstitial volume in oedema. Part II: Their effects at various abnormal steady-states.

A mathematical model has been used to investigate the alterations, in amount and importance, of the Factors controlling interstitial fluid volume in a number of steady-state oedemas. Steady-states were used because it is much easier to evaluate the effect of a specific Factor on oedema if all the others are constant. They are best compared if expressed in the same units: ml/min/100 g of tissue. The effects of lymphatic drainage on trauma are very important, as is the effect of tissue proteolysis on lymphoedema. Tissue proteolysis has minimal effects on the normal state and trauma; yet modelling its increase with benzo-pyrones markedly reduces oedema in both trauma and lymphoedema. Excess fibrosis greatly reduces lymphoedema. The effects of the individual Factors vary considerably between the different steady-states.

A model of the factors affecting interstitial volume in oedema. Part I: Hierarchies, some new factors and their equations.

A mathematical model has been constructed to investigate the alterations, in amount and in importance, of the Factors controlling interstitial fluid volume in a number of steady-state oedemas. There are many so-called "Safety Factors" (at least 15), including a whole group concerned with regulating the amount of protein in the tissues (and thus tissue colloidal osmotic pressure). They are often in long hierarchies (of even up to 11 Factors), each influencing the next. Sometimes a Factor is recursive, i.e., it influences itself (either positively or negatively) via a Hierarchy of other Factors. The effects of some Factors differ in different Hierarchies, i.e., an increase in the Factor will increase VI via some of the Hierarchies and decrease it via some other Hierarchies. Which effect is most important varies with the Hierarchies and conditions existing at the time. The Factors are best compared if expressed in the same units: ml/min/100g of tissue. This is possible via appropriate multiplication factors derived from the relevant equations.